b'Cellular and Molecular Neurobiologytissues, including ligaments, bone, cartilage, cervix, and the vagina (Feola etal. 2013; Moalli etal. 2008; Urbankova etal. 2018; Lin etal. 2018; Komatsuda etal. 2006; Chen etal. 2000), by influencing multiple pathways that modu-late cellular responses to mechanical loads (Li etal. 2014b; Richette etal. 2003) and the production of matrix metallo-proteinases and collagen (Elliot etal. 2008; Zong etal. 2007; Moalli etal. 2002). The importance of estrogen signaling and its response to mechanical loading has been highlighted by a study examining trabecular meshwork cells subjected to stretch from non-glaucomatous patients (Youngblood etal. 2020). Trabecular meshwork cells play an important role in outflow resistance and these cells differently expressed estro-gen receptor 1 after stretch (Youngblood etal. 2020). There-fore, it is likely that the effects of menopause and estrogen signaling on ocular biomechanical properties are mediated through similar, if not the same, pathways.Summary Fig. 8 Summary of the pathologies highlighted in this review, pro-portion of females in the affected population, and the current associa-Menopause is well known to be involved as a sex-specifiction with menopause. In cardiovascular disease (CVD), osteoporosis, risk factor in the pathogenesis of multiple systemic diseases,and osteoarthritis (OA), menopause alone is considered a sex-specific factor and early menopause further increases the risk of developing such as cardiovascular disease, osteoarthritis, and osteopo- these pathologies. To date, menopause has not been determined to rosis (Fig.8). Menopause and estrogen signaling are alsobe associated with developing glaucoma and it is not a consideration known to affect the biomechanical properties of multiple tis- when monitoring glaucoma progression or when deciding on treat-sues, including the vagina, the cervix, ligaments, bones, andment. However, we highlight the similarities of glaucoma to these other pathologies and propose that menopause is potentially a novel cartilage (Feola etal. 2013; Moalli etal. 2008; Urbankovasex-specific risk factor for developing glaucoma in femalesu From Page 29etal. 2018; Lin etal. 2018; Komatsuda etal. 2006; Chen etal. 2000). Unfortunately, the role of menopause in glau-applications in the management coma and its effect on ocularof glaucoma. Further, as estro- ot biomechanical properties is nas clearly established. genisknowntobeneuropro-tective, it may potentially have In this review, we have highlighted multiple clinical and a role in the treatment of non-preclinical studies showing that menopause and estrogen glaucomatousopticneuropa-signaling influence IOP, RGC survival after injury, aque-thies,suchasischemicoptic ous humor outflow resistance, and ocular biomechanics neuropathy,compressiveoptic (Fig.9). Taken together, these studies strongly suggest thneuropathy, and traumatic optic at neuropathy.menopause and estrogen signaling modulate multiple fac-The authors added, The asso-tors known to be associated with the development of and ciationofmenopauseandits progression of glaucoma, including IOP, which is a major relationship to glaucoma has an causal risk factor for developing glaucoma (Fig.3).ever-growing body of literature. Understanding how men ThesimilaritiesofmenopauseFig. 9 Illustration of how menopausal status and estrogens influence opause influences the devel-(orovariectomy)inglaucomaproperties throughout the eye. Several of these are direct risk factors opment and progression of glaucoma may affect clinical withothermajorpathologiesfor developing glaucoma (e.g., increasing IOP and outflow resistance decision-making when evaluating a woman with glaucoma buildafoundationthatmeno- and decreasing ocular stiffness). However, the role of menopause and or who is considered a glaucoma suspect. Knowledge ofestrogen on inflammatory mediators and retinal ganglion cell survival pause,amajorlifeeventin a womans reproductive status (i.e., premenopausal, peri- likely plays a key role in long-term ocular health and visionwomen,maybeasex-specific menopausal, or postmenopausal) may influence a clinicians risk factor for glaucoma devel-decision about when to initiate IOP lowering therapies andSource: Douglass A, Dattilo M, Feola AJ. Evidence for Menopause as a Sex-Specific Risk Factor for Glaucoma. Cell Mol opmentand/orprogression. Further,inocularresearchtheNeurobiol. 2022 Jan 4. doi: 10.1007/s10571-021-01179-z. Epub ahead of print. PMID: 34981287.what is an appropriate therapeutic IOP target, given theestrogen-based treatment for glaucoma has been proposed consistency across laboratories, effects of menopause on IOP. In addition and potentially(Wei etal. 2012; Wu etal. 2020; Dewundara etal. 2016); animal models, and various injury models supportsattention to gender differences in quality and perfor-more important, further knowledge of the effects of meno- however, these treatments lack preclinical and clinical evi-the idea of menopause as a sex-specific risk factor formance measures to identify gaps in women veterans pause and estrogen signaling on glaucoma will likely leaddence to support their widespread use. Based on the litera-developing glaucoma that warrants more attention. quality of care, respond to the needs of the grow-to novel targets for glaucoma treatment. The concept of anture, glaucoma treatments developed around the impact of ThefindingsareespeciallysignificantforV ing women veteran population, and decrease gender Ahealthcare providers. Women represented less thanhealth disparities. 10%ofU.S.veteransin2017,accordingtothe1Douglass A, Dattilo M, Feola AJ. Evidence for Menopause as a 1 3 National Center for Veterans Analysis and Statistics,Sex-Specific Risk Factor for Glaucoma. Cell Mol Neurobiol. 2022 but the number of women veterans receiving VHAJan 4. doi: 10.1007/s10571-021-01179-z. Epub ahead of print. PMID: care has increased by 22.1%, from 423,642 in 201434981287.to 517,241 in 2018, according to a report last year in2Feola AJ, Fu J, Allen R, Yang V, Campbell IC, Ottensmeyer A, Ethier CR, Pardue M. Menopause exacerbates visual dysfunction in experi-Womens Health Issues. 3 mental glaucoma. Exp Eye Res. 2019 Sep;186:107706. doi: 10.1016/j.Looking forward, the VHA anticipates this popula- exer.2019.107706. Epub 2019 Jun 18. PMID: 31226338; PMCID: tion will continue to increase, from 9.4% of the U.S.PMC6900868.veteran population in 2015 to 16.3% of the U.S. vet- 3Marshall V, Stryczek KC, Haverhals L, Young J, Au DH, Ho PM, eran population by 2043, wrote the authors from theKaboli PJ, Kirsh S, Sayre G. The Focus They Deserve: Improving Women Veterans Health Care Access. Womens Health Issues. 2021 VA Northeast Ohio Healthcare System in ClevelandJul-Aug;31(4):399-407. doi: 10.1016/j.whi.2020.12.011. Epub 2021 and colleagues. Since 2006, the VHA has increasedFeb 10. PMID: 33582001.32'